The individual compositions processes utilizing and mixtures of which constitute the present invention, are well known individually. Thus, polymyxin compositions, most notably polymyxin B, are recognized anti-bacterial compounds. Polymyxin B is a cyclic polypeptide produced and secreted by Bacillus polymyxa. The anti-bacterial effect of this antibiotic is apparently based on its ability to increase the permeability of the cell wall of bacteria. This creates channels in the cell membrane, resulting in the leakage of small molecules, such as phosphates, out of the bacterial cell. However, polymyxin B's spectrum of activity is recognized as being limited to gram-negative rods, such as Pseudomonas, E. coli, Enterobacter, Klebsiella, Salmonella and Shigella. The Proteus group is resistant, as are gram-negative cocci and all gram-positive bacteria, in common with yeast and fungi. Apparently the thickness of the cell wall of bacteria affects the ability of polymyxin to permeate the wall and reach the cell membrane.
Polymyxins are produced by the growth of Bacillus polymyxa. A plurality of isomers are found to be present, and thus the family of polymyxins is presently known to consist of polymyxin A, B, C, D and E, the last named also being known by the by the name, colistin. However, polymyxin B is most commonly used. It is quite water soluble and is stable such that a solution of polymyxin B can be maintained under refrigeration for one year without the loss of substantial anti-bacterial activity. While the individual experiments on which the present invention is based have taken place using polymyxin B, which has the greatest anti-bacterial activity of the polymyxins, when the term, polymyxin composition is used herein, it is intended that it cover not only polymyxin B, but other polymyxins such as polymyxins A and E.
Ciprofloxacin, sometimes marketed in the form of its HCl salt, is another well-known antibiotic. It is a broad spectrum antimicrobial agent that is active again certain, but not all Gram-positive and Gram-negative bacteria, including anthrax. Chemically it is a fluoroquinolone; in acid form it is 1-cyclopropyl-6-fluoro-1,4-dihyro-4-oxo-7-(1-piperaznyl)-3-quinolinecarboxylic acid. It is marketed under the trademark CIPRO as the monohydrochloride, monohydrate salt of the acid. As used herein, the term, ciprofloxacin will be used to refer to both the acid and its salt. It is believed to stop the multiplication of bacteria by inhibiting the reproduction and repair of their DNA.
Tobramycin is another broad spectrum antibiotic, categorized as an aminoglycoside. Its chemical formula is O-3-amino-3-deoxy-α-D-glucopyranosyl-(1□4)-O-[2/6-diamino-2,3,6-trideoxy-α-D-ribo-hexopyransol-(1□6)]-)]-2-deoxy-L-streptamine. While it is used to treat a variety of bacterial infections, it has found a special use in treating eye infections, alone or as a combination product in the form of a suspension or ointment.
The other, basic ingredient that forms the basis of my antibacterial composition and process is a hops composition. The hops plant, Humulus lupulus, is a twining vine that is a member of the mulberry family (Cannabinaceae). The female hop plant has inconspicuous flowers, and forms glandular, cone-shaped catkins which, when ripe and dried, find familiar use to impart a bitter flavor to beverages derived from malt. Hop has been used to flavor and preserve wort and beer since the 12th century in Germany and the 15th century in England. Its resins, which reside in the yellow glands of its cones, are known to possess antimicrobial properties. Those resins are extracted from the cones, usually by supercritical carbon dioxide treatment or by extraction with organic solvents. Today they, or in their preisomerized form, are frequently added for the bittering of beer in place of the hop flowers and hop pellets previously utilized.
With respect to the chemical nature of hop compounds, these are weak acids classified as alpha and beta resins or bitter acids. Alpha bitter acids are represented by humulone and its cogeners, cohumulone, adhumulone, prehumulone and posthumulone. The beta resins are represented by lupulone, often referred to as lupulon, and its cogeners, colupulone, adlupulone, and prelupulone. The alpha and beta acids have alicyclic structures (2,4-cyclohexodine-1-one), but their cogeners differ in the nature of the acyl side chains. While the alpha acids and their derivatives, the iso acids, contribute most to the bitterness of beer, there are many other, sometimes minor constituents that contribute to preservation and bitterness. One of these compounds is xanthohumol, a compound that falls within the scope of the present invention.
The antimicrobial properties of hop compounds are well-known; their extracts having been used to inhibit the growth of most gram positive microbes, and they are usually inactive against gram negative microbes. Yeast is not inhibited by hop compounds. Fungi are either not inhibited or inhibited only at unfavorably high concentrations of hop extracts. As the term, hop composition, is used herein, it is meant to cover the primary hop compounds, humulone, lupulone as well as xanthohumol, and their cogeners and isomers, either in pure form or as extracts, as well as iso and other derivatives and mixtures of the above.